Palbociclib-mediated cell cycle arrest can occur in the absence of the CDK inhibitors p21 and p27

Mapping Intimacies ◽

10.1101/2021.05.06.442976 ◽

2021 ◽

Author(s):

Betheney R Pennycook ◽

Alexis R Barr

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Mechanism Of Action ◽

Quantitative Imaging ◽

Cancer Therapies ◽

Cycle Arrest ◽

Wide Range ◽

Cast Doubt ◽

A Cell ◽

G1 Cell Cycle Arrest

The use of CDK4/6 inhibitors in the treatment of a wide range of cancers is an area of ongoing investigation. Despite their increasing clinical use, there is limited understanding of the determinants of sensitivity and resistance to these drugs. Recent data has cast doubt on how CDK4/6 inhibitors arrest proliferation, provoking renewed interest in the role(s) of CDK4/6 in driving cell proliferation. As the use of CDK4/6 inhibitors in cancer therapies becomes more prominent, an understanding of their effect on the cell cycle becomes more urgent. Here, we investigate the mechanism of action of CDK4/6 inhibitors in promoting cell cycle arrest. Two main models explain how CDK4/6 inhibitors cause G1 cell cycle arrest, which differ in their dependence on the CDK inhibitor proteins p21 and p27. We have used live and fixed single-cell quantitative imaging, with inducible degradation systems, to address the roles of p21 and p27 in the mechanism of action of CDK4/6 inhibitors. We find that CDK4/6 inhibitors can initiate and maintain a cell cycle arrest without p21 or p27. This work clarifies our current understanding of the mechanism of action of CDK4/6 inhibitors and has implications for cancer treatment and patient stratification.

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Palbociclib-mediated cell cycle arrest can occur in the absence of the CDK inhibitors p21 and p27

Open Biology ◽

10.1098/rsob.210125 ◽

2021 ◽

Vol 11 (11) ◽

Author(s):

Betheney R. Pennycook ◽

Alexis R. Barr

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Mechanism Of Action ◽

Quantitative Imaging ◽

Cancer Therapies ◽

Cycle Arrest ◽

Wide Range ◽

Cast Doubt ◽

A Cell ◽

G1 Cell Cycle Arrest

The use of CDK4/6 inhibitors in the treatment of a wide range of cancers is an area of ongoing investigation. Despite their increasing clinical use, there is limited understanding of the determinants of sensitivity and resistance to these drugs. Recent data have cast doubt on how CDK4/6 inhibitors arrest proliferation, provoking renewed interest in the role(s) of CDK4/6 in driving cell proliferation. As the use of CDK4/6 inhibitors in cancer therapies becomes more prominent, an understanding of their effect on the cell cycle becomes more urgent. Here, we investigate the mechanism of action of CDK4/6 inhibitors in promoting cell cycle arrest. Two main models explain how CDK4/6 inhibitors cause G1 cell cycle arrest, which differ in their dependence on the CDK inhibitor proteins p21 and p27. We have used live and fixed single-cell quantitative imaging, with inducible degradation systems, to address the roles of p21 and p27 in the mechanism of action of CDK4/6 inhibitors. We find that CDK4/6 inhibitors can initiate and maintain a cell cycle arrest without p21 or p27. This work clarifies our current understanding of the mechanism of action of CDK4/6 inhibitors and has implications for cancer treatment and patient stratification.

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PPAR-γ ligands induce G1 cell cycle arrest and reduce ornithine decarboxylase activity of human Barrett's adenocarcinoma cells

Gastroenterology ◽

10.1016/s0016-5085(01)82062-x ◽

2001 ◽

Vol 120 (5) ◽

pp. A415-A415

Author(s):

T TAKASHIMA ◽

Y FUJIWARA ◽

K HIGUCHI ◽

T ARAKAWA ◽

Y YANO ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Ornithine Decarboxylase ◽

Decarboxylase Activity ◽

Ornithine Decarboxylase Activity ◽

Ppar Γ ◽

Cycle Arrest ◽

Adenocarcinoma Cells ◽

Barrett’S Adenocarcinoma ◽

G1 Cell Cycle Arrest

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Polyphyllin I Induces Cell Cycle Arrest and Cell Apoptosis in Human Retinoblastoma Y-79 Cells through Targeting p53

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520618666180108095148 ◽

2018 ◽

Vol 18 (6) ◽

pp. 875-881 ◽

Cited By ~ 7

Author(s):

Xue Zhu ◽

Ke Wang ◽

Kai Zhang ◽

Yi Pan ◽

Fanfan Zhou ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Cell Apoptosis ◽

Potential Effect ◽

External Beam Radiation ◽

Beam Radiation ◽

P53 Expression ◽

Cycle Arrest ◽

Wide Range ◽

Human Retinoblastoma

Background: Retinoblastoma is the most common intraocular malignant tumor in childhood. Although external beam radiation and enucleation are effective to control retinoblastoma, eye salvage and vision preservation are still significant challenges. Polyphyllin I (PPI), a natural compound extracted from Paris polyphylla rhizomes, has a wide range of activities against many types of cancers. However, the potential effect of this herbal compound on retinoblastoma has not yet been investigated. Method: In the present study, we evaluated the cytotoxic effect of PPI on human retinoblastoma Y-79 cells as well as its underlying molecular mechanism. Our results indicated that PPI treatment significantly inhibited cell proliferation, arrested the cell cycle at G2/M phase and induced cell apoptosis of Y79 cells through the mitochondrial- dependent intrinsic pathway. Moreover, p53 is involved in PPI-induced cytotoxicity in human retinoblastoma Y-79 cells. Exposure to 10 μM PPI for 48 h dramatically induced the expression levels of p53, phosphorylated- p53 and acetylated-p53. Furthermore, blockade of p53 expression effectively attenuated PPI-induced cell cycle arrest and cell apoptosis in Y-79 cells. Result: These results demonstrated that PPI exhibits anti-proliferation effect on human retinoblastoma Y-79 cells through modulating p53 expression, stabilization and activation. This information shed light on the potential application of PPI in retinoblastoma therapy.

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HIV-1 Vpr activates host CRL4-DCAF1 E3 ligase to degrade histone deacetylase SIRT7

Virology Journal ◽

10.1186/s12985-021-01514-2 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Xiaohong Zhou ◽

Christina Monnie ◽

Maria DeLucia ◽

Jinwoo Ahn

Keyword(s):

Cell Cycle ◽

Dna Repair ◽

Cell Cycle Arrest ◽

Histone Deacetylase ◽

E3 Ligase ◽

Cycle Arrest ◽

Wide Range ◽

In Vitro Reconstitution ◽

Hiv 1

Abstract Background Vpr is a virion-associated protein that is encoded by lentiviruses and serves to counteract intrinsic immunity factors that restrict infection. HIV-1 Vpr mediates proteasome-dependent degradation of several DNA repair/modification proteins. Mechanistically, Vpr directly recruits cellular targets onto DCAF1, a substrate receptor of Cullin 4 RING E3 ubiquitin ligase (CRL4) for poly-ubiquitination. Further, Vpr can mediate poly-ubiquitination of DCAF1-interacting proteins by the CRL4. Because Vpr-mediated degradation of its known targets can not explain the primary cell-cycle arrest phenotype that Vpr expression induces, we surveyed the literature for DNA-repair-associated proteins that interact with the CRL4-DCAF1. One such protein is SIRT7, a deacetylase of histone 3 that belongs to the Sirtuin family and regulates a wide range of cellular processes. We wondered whether Vpr can mediate degradation of SIRT7 via the CRL4-DCAF1. Methods HEK293T cells were transfected with cocktails of plasmids expressing DCAF1, DDB1, SIRT7 and Vpr. Ectopic and endogeneous levels of SIRT7 were monitered by immunoblotting and protein–protein interactions were assessed by immunoprecipitation. For in vitro reconstitution assays, recombinant CRL4-DCAF1-Vpr complexes and SIRT7 were prepared and poly-ubiqutination of SIRT7 was monitored with immunoblotting. Results We demonstrate SIRT7 polyubiquitination and degradation upon Vpr expression. Specifically, SIRT7 is shown to interact with the CRL4-DCAF1 complex, and expression of Vpr in HEK293T cells results in SIRT7 degradation, which is partially rescued by CRL inhibitor MNL4924 and proteasome inhibitor MG132. Further, in vitro reconstitution assays show that Vpr induces poly-ubiquitination of SIRT7 by the CRL4-DCAF1. Importantly, we find that Vpr from several different HIV-1 strains, but not HIV-2 strains, mediates SIRT7 poly-ubiquitination in the reconstitution assay and degradation in cells. Finally, we show that SIRT7 degradation by Vpr is independent of the known, distinctive phenotype of Vpr-induced cell cycle arrest at the G2 phase, Conclusions Targeting histone deacetylase SIRT7 for degradation is a conserved feature of HIV-1 Vpr. Altogether, our findings reveal that HIV-1 Vpr mediates down-regulation of SIRT7 by a mechanism that does not involve novel target recruitment to the CRL4-DCAF1 but instead involves regulation of the E3 ligase activity.

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